The expression and proliferation of drug-resistant tumor cells, i.e., tumor cells which cytotoxic agents have no appreciable ability to kill at concentrations that are tolerable to normal host tissue, are considered to be a major cause of failure in cancer chemotherapy. Generally, resistance is acquired through multiple mechanisms under the selection pressure of chemotherapy. Multi-drug resistance (MDR) characterizes a complex cell phenotype, the predominant feature of which is resistance to a wide range of cytotoxic agents, many of which are anti-cancer drugs. The in vivo MDR can be mimicked in vitro by developing and selecting resistant mammalian cell lines. Although resistance is developed to a single drug, the cells show cross-resistance to a variety of structurally unrelated compounds. The factors underlying the development of resistance are multiple and include: 1) over-expression of a membrane glycoprotein, gp 170; 2) alteration in drug uptake; 3) alteration in drug binding to target sites; 4) increased efflux of drug; 5) alteration in cellular metabolism resulting in activation or inactivation of drug, and 6) alterations in DNA repair mechanisms.
Despite the complexity of MDR and the heterogeneity of tumor cells, some calcium channel blockers, e.g., verapamil (perhaps the most studied for clinical application), diltiazem, nicardipine and nifedipine, phenothiazines, and calmodulin inhibitors as agents to enhance resistant cells chemosensitivity have been studied. See e.g. Helson, Cancer Druo Delivery 1:353-61 (1984); Tsurno et al., Cancer Research 43:2905-10 (1983); Bessho et al., Medical and Pediatric Oncology 13:199-202 (1985).
Also, metastasis, in cancer, the appearance of neoplasms in parts of the body remote from the seat of the primary tumor, is a problem recurring in cancer treatment. It results from dissemination of tumor cells by the lymphatics or blood vessels, or through serous cavities or subarachnoid or other spaces, and if widespread, usually renders the cancer incurable by surgery alone.
Some literature in the art reports that calcium channel blockers may represent a new class of antimetastatic agents with several attractive features, including low chronic toxicity, oral administration capability, clinical trial stage research, and/or already approved for cardiovascular disease. See e.g., Honn et al., Biochem Pharm. 34:235-41 (1985); Tsuruo et al., Cancer Chemother. Pharmacol. 14:30-3 (1985); Onoda et al., Cancer Lett. 30 181-8 (1986); Onoda et al., Proc. Annu. Meet. Am. Assoc. Cancer Res. 25:351 (1984); Honn et al., Proc. Soc. Exp. Biol. Med. 174:16-9 (1983); Honn et al., "Treatment of Metastasis: Problems and Prospects," London, Taylor and Francis, (1984) pp. 259-62; Pauwels-Vergely et al., Fourth European Conference on Clinical Oncology and Cancer Nursing, Madrid, Nov. 1-4, 1987, Federation of European Cancer Societies, 1987, p. 88.
Still, the art lacks and needs improved cancer drug potentiators. The art lacks and needs further treatments for metastasis.